The response to a severe burn is characterized by a persistent hypermetabolic and catabolic state that results in massive loss of muscle tissue, even in the fed state. In patients with > 30% of total body surface area burned, protein breakdown persists for approximately one year after the burn wound is 95% healed. Endogenous catecholamines have been implicated as primary mediators of the hypermetabolic response to trauma or burn. Chronic elevation of plasma catecholamine levels may result in the development of hyperdynamic circulation, increased basal energy expenditure, peripheral insulin resistance with hyperglycemia, increased peripheral lipolysis, depressed immune function, skeletal muscle protein catabolism and hypertrophic scarring. The hypermetabolic response to burns is also characterized by a profound tachycardia and increased cardiac work that are detrimental to the heart. The persistence of tachycardia and muscle catabolism significantly compromises rehabilitation and results in an excessive delay before resuming normal physical and functional activities. Treatments are critically needed to decrease hypermetabolism, hyperdynamic circulation and catabolism of lean mass. In this National Institutes of Health defined, phase II clinical trial, we will study the efficacy, effects and mechanisms of the reduction in post-burn catecholamine surge by the non-selective Beta-1 (-1) and Beta-2 (-2) adrenergic antagonist, propranolol in severely burned children and adults. This synergistic program involves seven interrelated projects, in which cellular and tissue responses will be assessed to determine proteomic profiles driving the clinical phenotypes and patient outcomes. We hypothesize that catecholamines are a primary mediator of the post-burn catabolic and hypermetabolic responses, and that these responses will be attenuated by the therapeutic use of propranolol, administered for one year post burn. To achieve this we have assembled a group of clinicians and scientists, experts in their fields that will work as a collaborative team to assess the immunoinflammatory, metabolic, psychological response and correlate these with protein signaling, wound healing and functional data. The uniqueness and innovation of this P50 Burn Center project is that for the first time, the fundamental mechanisms of the burn-induced stress phenotype and response to a targeted pharmacological intervention that attenuates this catabolic response will be elucidated. Further, this P50 Burn Center will translate this improved understanding and knowledge to clinical outcomes of burns in order to improve the standard of burn care. PUBLIC HEALTH RELEVANCE: There has been a dearth of inexpensive, yet effective therapeutic interventions for burns that improve so many long-term outcomes. The findings of this long-term clinical trial will advance the understanding of burn-induced tissue-specific signaling pathways, alterations in clinical indices such as insulin resistance, body composition, scarring, and protein and hormonal bio-signatures, and will improve clinical outcomes of burn patients, and by extension also improve these in other hypermetabolic and hypercatabolic states.